We attempted to define the immune response to the dengue type 4, strain 814669, envelope glycoprotein (E) in Balb/c (H-2 d) and CBA/N or Balb/K (H-2 k) mice using 38 synthetic 15-amino-acid peptides that span the E sequence (previously described). An in vivo assay in which mice were immunized with peptide(s) followed by infectious dengue virus and an in vitro assay of proliferation in response to peptides of T lymphocytes isolated from virus immunized mice were conducted. Peptides 39 (amino acids 137 to 151) and 41 (158-172) elicited high titer peptide and dengue 4 virus binding antibodies in Balb/c mice, as measured by ELISA. Peptides B (30-55) and 53 (368-382) elicited IgG class peptide-binding antibodies only. Peptide 54 (381-395) appeared to contain a T cell epitope only. In CBA/N or Balb/k mice, peptide 67 (17-30) elicited a response comparable to that of peptides 39 and 41 in Balb/c mice. Peptides 53 and 72 (233-246) elicited high titer IgG peptide antibodies only. Although the T cell proliferation assay has not yet worked well in H-2 k mice, it is apparent that all these peptides contain T cell epitopes as defined in that assay. Peptides 67, 52 (356-369), and 53 were to varying degrees immunogenic in both H-2 d and H-2 k mice. Additional data show that priming with a given peptide in the in vivo assay could result in an anamnestic response to linear epitopes not included on the priming peptide, shortly after the mice were given infectious dengue 4 virus intraperitoneally.